The long-term objective of this proposal is to determine the cellular bsis for compensatory changes in the sensitivity of smooth muscle and cardiac muscle to drugs. Knowledge of the physiology and pharmacology of these tissues will be applied to determine the manner in which membrane-potential dependent and independent processes are altered to make the cells more sensitive. Such compensatory changes appear to be involved in the development of tolerance to several classes of drugs and may also play a role in the development of pathological processes such as hypertension. The specific aims include the following: 1. To identify the sources of calcium for contraction of the normal and supersensitive vas deferens. 2. To assess the potential role of changes in affinity and/or density of alpha-adrenoceptors in the supersensitive smooth muscle of the bas deferens. 3. To determine whether there are alterations in the number of Na+,K+ pump sites in supersensitive and hypertensive vascular smooth muscle. 4. To determine the role of electrophysiologic factors, especially electrogenic Na+,K+ pumping, in chronotropic supersensitivity of the guinea-pig heart. Methods to be used include, among others: (a) The measurement of the responses of smooth muscle to drugs in the presence and absence of calcium and in the presence and absence of inhibitors of calcium flux. (b) The determination of the binding of radioactive ligands (such as 3H-dihydroergo cryptine and 3H-ouabain) to smooth muscle membrane fractions. (c) Intracellular recording in cardiac cells with microelectrodes and related electrophysiologic methods.